This is a systematic long-term research program with two interwoven themes. First, the development of mild chemical methods for peptide synthesis. The theoretical basis of these studies is the concept of orthogonal protection, and the experimental cornerstones are the new NAlpha-dithiasuccinoyl-(Dts) amino protecting group and the related class of open-chain carbamoyl disulfides of primary and secondary amines. These protecting groups can be rapidly and quantitatively removed under neutral conditions by reduction with thiols and other agents. A complete set of orthogonally protected NAlpha-Dts amino acid derivatives shall be prepared and applied to the synthesis of biologically active peptides. As a culmination of this line of res0arch, the first total synthesis of an iron-sulfur protein, namely crystalline ferredoxin (55 residues) shall be attempted. Amino acid replacement analogues of this protein are contemplated which may shed light on the molecular details of electron transport. The principles of orthogonal solid-phase peptide synthesis shall be further elaborated by the development of new anchoring linkages and new thiolysable side-chain protecting groups. These methods will further facilitate the preparation of fragile and structurally complex biomolecules. The mild and specific chemistry of thiolyses of dithiasuccinoyl-amines and carbamoyl disulfides will be exploited in a series of biochemically oriented studies which comprise the second theme of the research. Applications are foreseen for intracellular drugs delivery, for the directed synthesis of unsymmetrical disulfdes, and for the functional differentiation of Alpha- and epsilon-amino groups of peptides and proteins. Some of these lines of inquiry, if fruitful, could lead to clinically useful drug therapies.